During the past decade, the relationship between monoamine uptake and a variety of diseases and conditions has been appreciated and investigated. For example, the hydrochloride salt of fluoxetine (dl-N-methyl-3-[4-(trifluoromethyl)phenoxy]-3-phenylpropylamine) is a selective serotonin (5-hydroxytryptamine, 5HT) uptake inhibitor. Fluoxetine hydrochloride is marketed under the trademark PROZAC.RTM. for the treatment of depression. This compound is among many taught in U.S. Pat. Nos. 4,018,895, 4,194,009, and 4,314,081 as being potent, selective blockers of serotonin uptake.
Fluoxetine is a racemate of the two enantiomeric forms. The biological and pharmacological activity of each enantiomer has been found to be essentially the same; see, Robertson et al., J. Med. Chem., 31, 1412 (1988) and references cited therein.
Norfluoxetine [3-(4-trifluoromethylphenoxy)-3-phenylpropylamine] is a metabolite of fluoxetine and is known to block monoamine uptake, especially serotonin. See U.S. Pat. No. 4,313,896. Since it is a metabolite of fluoxetine, it is believed that this compound contributes in part to the biological activity seen upon chronic administration of fluoxetine.
In copending application Ser. No. 07/486,478, filed Feb. 28, 1990, now abandoned, it was observed that (S)-norfluoxetine is substantially more active than its (R)-antipode as a serotonin uptake inhibitor. We have now discovered that the (R)-enantiomer of norfluoxetine is a selective agonist of 5HT.sub.1C receptors.